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Bacterial Meningitis 2
Advances in treatment of bacterial meningitis
Diederik van de Beek, Matthijs C Brouwer, Guy E Thwaites, Allan R Tunkel

Bacterial meningitis kills or maims about a fth of people with the disease. Early antibiotic treatment improves Lancet 2012; 380: 1693702
outcomes, but the eectiveness of widely available antibiotics is threatened by global emergence of multidrug-resistant See Comment page 1623
bacteria. New antibiotics, such as uoroquinolones, could have a role in these circumstances, but clinical data to This is the second in a Series of
support this notion are scarce. Additionally, whether or not adjunctive anti-inammatory therapies (eg, dexamethasone) three papers about bacterial
meningitis
improve outcomes in patients with bacterial meningitis remains controversial; in resource-poor regions, where the
disease burden is highest, dexamethasone is ineective. Other adjunctive therapeutic strategies, such as glycerol, Department of Neurology,
Center for Infection and
paracetamol, and induction of hypothermia, are being tested further. Therefore, bacterial meningitis is a substantial Immunity Amsterdam
and evolving therapeutic challenge. We review this challenge, with a focus on strategies to optimise antibiotic ecacy (CINIMA), Academic Medical
in view of increasingly drug-resistant bacteria, and discuss the role of current and future adjunctive therapies. Center, University of
Amsterdam, Amsterdam,
Netherlands
Introduction therapy. Furthermore, vancomycin is expensive and rarely (Prof D van de Beek MD,
Acute bacterial meningitis is a life-threatening infectious available in low-income countries.7 Alternative agents in M C Brouwer MD); Department
disease, the epidemiology of which has changed sub- these settings include an antipneumococcal uoro- of Infectious Diseases/Centre
stantially since the introduction of conjugate vaccines.13 quinolone (eg, moxioxacin) and rifampicin, although for Clinical Infection and
Diagnostics Research, Kings
Nevertheless, the disease continues to inict a heavy toll, clinical data to support the use of these drugs are scarce. College London, London, UK
including in high-income countries, causing substantial Rifampicin is inexpensive, widely available, penetrates (G E Thwaites MD); Guys and
morbidity and mortality.1,4 Early administration of anti- reasonably well into cerebrospinal uid (CSF), and usually St Thomas NHS Foundation
Trust, London, UK
biotics saves lives, but the global emergence of multidrug- has in-vitro activity against ceftriaxone-resistant pneumo-
(G E Thwaites); and Department
resistant bacteria threatens the eectiveness of many coccal strains.4,8 of Medicine, Monmouth
inexpensive and widely available antibiotics. The role of Listeria monocytogenes is noteworthy because of its Medical Center, Long Branch,
adjunctive anti-inammatory therapies is uncertain, resistance to cephalosporins. Amoxicillin or ampicillin NJ, USA (Prof A R Tunkel MD)
especially in resource-poor settings. For these reasons, are eective against Listeria spp and should be given to Correspondence to
bacterial meningitis is an evolving therapeutic challenge. immunosuppressed patients with meningitis who are at Prof Diederik van de Beek,
Department of Neurology,
In this review, we discuss the various treatment strategies risk of this infection, including pregnant patients and Center of Infection and
available, and draw attention to advances in antibiotic those older than 50 years. Immunity Amsterdam (CINIMA),
and adjunctive therapy. Academic Medical Center,
University of Amsterdam,
Optimisation of the delivery and eectiveness PO Box 22660, 1100DD
Initial empirical antibiotics of antibiotics Amsterdam, Netherlands
Early clinical suspicion of bacterial meningitis and rapid Optimisation of the delivery and eectiveness of anti- d.vandebeek@amc.uva.nl
administration of antibiotics is important to increase biotics are two key therapeutic challenges in bacterial
survival and reduce morbidity. In a prospective study of meningitis. Penetration across the bloodbrain barrier is
156 patients with pneumococcal meningitis admitted to important for successful treatment and depends on the
an intensive-care unit,5 a delay in antibiotic treatment of amount of disruption of the barriers integrity by inam-
longer than 3 h after arrival at the hospital was associated mation, and the size, charge, lipophilicity, protein-
with increased 3-month mortality. binding ability, and interaction with eux pumps of the
Administration of empirical antibiotics for patients antibiotic (table 2).8,9 However, clinical ecacy also
with bacterial meningitis should be based on local epi-
demiology, the patients age, and the presence of specic
underlying diseases or risk factors (table 1).4,6 In Search strategy and selection criteria
geographical regions with Streptococcus pneumoniae We searched the Cochrane Library (The Cochrane Library 2011, issue 1), Medline
(pneumococcal) strains that are resistant to penicillin and (1966 to March, 2012), and Embase (1974 to March, 2012). We used the search terms
cephalosporins (gure), patients older than 1 month with bacterial meningitis or meningitis with the terms therapy or antibiotics or
community-acquired bacterial meningitis should receive antimicrobial or treatment. We mainly selected articles published in the past
vancomycin plus a third-generation cephalosporin (either 5 years, but did not exclude commonly referenced and highly regarded older
cefotaxime or ceftriaxone). The decision of whether to use publications. We also searched the reference lists of articles identified by this search
vancomycin depends on the rate of resistance to third- strategy and selected those that we judged to be relevant. Review articles and book
generation cephalosporins. In areas where the prevalence chapters are cited to provide readers with more details and more references than can
of cephalosporin-resistant S pneumoniae is low (<1% be included in this paper. We modified our reference list on the basis of comments
resistance), a third-generation cephalosporin (either cefo- from peer reviewers.
taxime or ceftriaxone) usually suces as empirical

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Bacterial pathogens Empirical therapy Intravenous dose (dose interval)

Community-acquired meningitis
Age <1 month Streptococcus agalactiae, Escherichia coli,
Listeria monocytogenes
Age 123 months S agalactiae, E coli, S pneumoniae, Neisseria
meningitidis
Age 250 years S pneumoniae, N meningitidis
Age >50 years S pneumoniae, N meningitidis,
L monocytogenes, aerobic Gram-negative
bacilli
Immunocompromised S pneumoniae, N meningitidis,
state L monocytogenes, Staphylococcus aureus,
Salmonella spp, aerobic Gram-negative bacilli
(including Pseudomonas aeruginosa)
Recurrent S pneumoniae, N meningitidis,
Haemophilus inuenzae
Health-care-associated meningitis
Basilar skull fracture S pneumoniae, H inuenzae, group A
-haemolytic streptococci
Head trauma; Staphylococci (S aureus and
post-neurosurgery coagulase-negative staphylococci), aerobic
Gram-negative bacilli (including P aeruginosa)
Amoxicillin/ampicillin plus Age <1 week: ampicillin 150 mg/kg per day (8 h); cefotaxime 100150 mg/kg
cefotaxime, or amoxicillin/ per day (812 h); gentamicin 5 mg/kg per day (12 h)
ampicillin plus an aminoglycoside Age 14 weeks: ampicillin 200 mg/kg per day (68 h); gentamicin 75 mg/kg per
day (8 h); tobramycin 75 mg/kg per day (8 h); amikacin 30 mg/kg per day (8 h);
cefotaxime 150200 mg/kg per day (68 h)
Vancomycin plus a third-generation Vancomycin 60 mg/kg per day (6 h) to achieve serum trough concentrations of
cephalosporin (either cefotaxime or 1520 g/mL; cefotaxime 225300 mg/kg per day (68 h); ceftriaxone
ceftriaxone)* 80100 mg/kg per day (1224 h)
Vancomycin plus a third-generation Children as above; adults: vancomycin 3060 mg/kg per day (812 h) to achieve
cephalosporin (either cefotaxime or serum trough concentrations of 1520 g/mL; ceftriaxone 4 g per day (12 h);
ceftriaxone)* cefotaxime 812 g per day (46 h); cefepime 6 g per day (8 h); ceftazidime 6 g
per day (8 h); amoxicillin or ampicillin 12 g per day (4 h); penicillin 24 million
units per day (4 h); meropenem 6 g per day (8 h)
Vancomycin plus ampicillin plus a As for adults above
third-generation cephalosporin
(either cefotaxime or ceftriaxone)
Vancomycin plus ampicillin plus
either cefepime or meropenem
Vancomycin plus a third-generation
cephalosporin (either cefotaxime or
ceftriaxone)
Vancomycin plus a third-generation
cephalosporin (either cefotaxime or
ceftriaxone)
Vancomycin plus ceftazidime,
cefepime, or meropenem

Preferred daily intravenous doses (and dosing intervals) apply to patients with normal renal and hepatic function. In patients with impaired renal function, the loading (initial) dose of the antibiotic is based on
the extracellular uid volume and is not changed in the case of decreased renal function; subsequent doses or dosing intervals need to be changed in patients with impaired renal function. *Add amoxicillin or
ampicillin if meningitis caused by L monocytogenes is also suspected.

Table 1: Empirical antibiotics for presumed bacterial meningitis by demography and risk factor

depends on the antibiotic CSF concentration and its
bactericidal activity against causative bacteria.8 For
example, although -lactam antibiotics penetrate poorly
into the CSF, very eective bactericidal concentrations
can be achieved by administration of frequent and high
systemic doses, which are generally well tolerated.8
Toxicity makes dose escalation dicult for the amino-
glycosides, glycopeptides, and polymyxins; therefore,
intrathecal or intraventricular administration of these
agents might be needed to reach eective CSF con-
centrations, although data to support the safety and
ecacy of this approach are scarce.10 The intrathecal
route resulted in high CSF aminoglycoside con-
centrations in young children with gram-negative
meningitis,11 but a controlled, non-randomised study of
intrathecal versus intravenous gentamicin in 117 infants
with Gram-negative meningitis did not show clinical
benet.12 Furthermore, in a randomised controlled trial
of intraventricular versus systemic gentamicin, investi-
gators reported a substantially higher mortality rate in
patients receiving intraventricular gentamicin therapy
(43% vs 13%).13
A better understanding of the relation between CSF
concentration and antibiotic eectiveness could improve
clinical outcomes. Almost 60 years ago, Eagle and
colleagues14 showed that penicillin killed bacteria more
eectively when given continuously rather than by bolus
injections; the best predictor of successful treatment was
the time that concentrations were maintained above the
minimum inhibitory concentration (MIC). Some studies
have investigated whether continuous infusions of these
antibiotics improve outcomes in patients with bacterial
meningitis.15 A possible benet of continuous cefotaxime
infusion was suggested in a study of 723 African children
with bacterial meningitis randomly assigned to either
cefotaxime boluses or continuous cefotaxime infusion
for the rst 24 h of therapy;16 272 (38%) children died, but
the mode of cefotaxime administration did not signi-
cantly change the proportion of children who died or
were severely disabled by hospital discharge. However, a
planned subgroup analysis showed that children with
pneumococcal meningitis given continuous cefotaxime
infusion were signicantly less likely to die or have
sequelae than were those given cefotaxime boluses.

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<1%
15%
>5%
no data available
Figure: Global rates of pneumococcal penicillin resistance
Antibiotics for specic organisms
Once a bacterial pathogen has been identied on a CSF
Gram stain, or isolated and in-vitro susceptibility testing
done, antibiotic therapy can be modied further for
optimum treatment (tables 3 and 4).
Streptococcus pneumoniae
The treatment of pneumococcal meningitis has changed
since the emergence of strains with reduced susceptibility
to penicillin (gure); the prevalence of reduced suscept-
ibility ranges from 25% to more than 50% in some US
regions and is even higher in many other countries.17
Penicillin resistance is a marker of decreased susceptibility
to other antibiotics, which could lead to treatment failures
in patients with pneumococcal meningitis.18 In areas
with cephalosporin resistance, empirical therapy for
pneumococcal meningitis should consist of vancomycin
combined with either cefotaxime or ceftriaxone, pending
results of in-vitro susceptibility testing. Although rates of
pneumococcal meningitis have decreased since the
introduction of the heptavalent pneumococcal conjugate
vaccine, the number of patients with meningitis caused
by serotypes not covered by the vaccine, including
resistant strains, has increased.19 Non-vaccine serotypes
are generally more susceptible to antibiotics than are
vaccine serotypes, except for serotype 19A.19
Adequate doses of vancomycin are important to achieve
appropriate CSF concentrations, because concomitant use
of adjunctive dexamethasone could reduce vancomycin
penetration into CSF. In a study of 14 patients with bac-
terial meningitis who were receiving adjunctive dexa-
methasone, administration of intravenous vancomycin
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Series
(15 mg/kg loading dose, followed by a continuous infusion
of 60 mg/kg per day), led to adequate CSF vancomycin
concentrations (mean 79 g/mL).20 Although clinical data
on the ecacy of rifampicin in patients with pneumococcal
meningitis are scarce, some authorities use this agent in
combination with a third-generation cephalosporin, with
or without vancomycin, in patients with pneumococcal
meningitis caused by strains that are likely to be highly
resistant to penicillin or cephalosporins.4
Once the MIC of penicillin and third-generation cephalo-
sporins is known, treatment can be modied accordingly
(table 4). The Clinical and Laboratory Standards Institute
has redened the in-vitro susceptibility breakpoints for
pneumococcal isolates from patients with meningitis as
either susceptible (MIC 006 g/mL) or resistant (MIC
012 g/mL) to penicillin;21 for penicillin-resistant strains,
the therapeutic approach depends on the degree of in-vitro
susceptibility to the third-generation cephalosporins.
Neisseria meningitidis
The current treatment recommendation for meningo-
coccal meningitis is penicillin G, amoxicillin, or ampi-
cillin.3,4,6 However, meningococcal strains with reduced
susceptibility to penicillin have been identied in many
countries. In a Spanish study,22 the investigators reported
an increase in the prevalence of meningococcal strains
with reduced susceptibility to penicillin from 91% in
1986, to 714% in 1997. By contrast, intermediate suscept-
ibility to penicillin (MIC >01 g/mL) has been reported
in 34% of US meningococcal isolates and 2% of isolates
in sub-Saharan Africa.23,24 In one study,25 investigators
recorded an association between reduced susceptibility to
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CSF penetration CSF penetration Comments on use of antibiotic class for meningitis treatment
(CSF:plasma)* in (drug in CSF:plasma)*
uninamed meninges in inamed meninges
-lactams Poor CSF penetration, but high systemic doses are well tolerated and attain CSF concentrations that greatly
exceed the MIC of susceptible bacteria. 40% of cefotaxime vs 90% of ceftriaxone is protein bound. Avoid
imipenem because it could lower the seizure threshold. Continuous infusions could enhance bacterial killing
Benzylpenicillin 002 01
Amoxicillin/ampicillin 001 005
Cefotaxime 01 02
Ceftriaxone 0007 01
Meropenem 01 03
Aminoglycosides Poor CSF penetration and toxicity limits increases in systemic doses. Consider intraventricular/intrathecal
delivery if needed
Gentamicin 001 01
Amikacin No data 01
Glycopeptides Poor CSF penetration and toxicity limits increases in systemic doses. Continuous infusions could enhance
bacterial killing. Limited data for intraventricular/intrathecal delivery
Vancomycin 001 02
Teicoplanin 001 01
Fluoroquinolones Good CSF penetration. Moxioxacin is an alternative agent for the treatment of penicillin-resistant
pneumococcal meningitis
Ciprooxacin 03 04
Moxioxacin 05 08
Levooxacin 07 08
Others
Chloramphenicol 06 07 Excellent CSF penetration, although toxicity concerns limit its use
Rifampicin 02 03 80% protein bound; CSF concentrations greatly exceed MIC of susceptible bacteria
Newer agents
Cefepime 01 02 Eective against penicillin-resistant pneumococcal meningitis
Linezolid 05 07 Case report/series suggest eectiveness for pneumococcal, staphylococcal, and enterococcal meningitis, although
high interindividual variability in CSF pharmacokinetics suggests therapeutic drug measurements could be needed
Daptomycin No data 005 Poor penetration, but CSF concentrations exceed MIC of susceptible bacteria; case reports/series suggest ecacy
in staphylococcal and enterococcal meningitis
Tigecycline No data 05 Good CSF penetration, but concentrations achieved at current standard doses could be insucient to ensure
bacterial killing

CSF=cerebrospinal uid. MIC=minimum inhibitory concentration. *Based on calculated area under the curve (AUC)CSF/AUCplasma when possible, but data are limited for most antibiotics and AUC cannot be
calculated on the basis of single CSF measurements. In these circumstances, CSF penetration is estimated from paired plasma and CSF measurements.

Table 2: Estimates of CSF penetration of antibiotics used for the treatment of bacterial meningitis8,9

in-vitro susceptibility testing are available. High-level

Antibiotic therapy
resistance to chloramphenicol (MIC 64 g/mL) has been
Gram-positive cocci in pairs Vancomycin plus a third-generation cephalosporin (either cefotaxime reported,26 but the incidence is low in most countries.27
or ceftriaxone)
Furthermore, ciprooxacin resistance has been described
Gram-negative cocci in pairs Third-generation cephalosporin (either cefotaxime or ceftriaxone)
in some regions of the USA,28 and has aected
Gram-positive bacilli Amoxicillin/ampicillin* or penicillin G*
recommendations for chemoprophylaxis. During menin-
Gram-positive cocci in chains Amoxicillin/ampicillin or penicillin G*
gococcal meningitis epidemics in resource-poor settings,
Gram-negative bacilli Third-generation cephalosporin one intramuscular injection of long-acting chloram-
*Consider the addition of an aminoglycoside. phenicol is sucient;27 an injection of ceftriaxone is
equally eective.29
Table 3: Recommended antibiotics in patients with community-acquired meningitis by result of
cerebrospinal uid Gram stain
Listeria monocytogenes
Amoxicillin, ampicillin, or penicillin G is the treatment
penicillin and an increased risk of death or neurological of choice for Listeria meningitis.30 Some authorities have
sequelae in children with meningococcal meningitis. recommended the addition of an aminoglycoside
Therefore, patients with meningococcal meningitis because of enhanced in-vitro killing and in-vivo synergy
should be treated empirically with a third-generation in animal models. No study has been done to compare
cephalosporin (cefotaxime or ceftriaxone) until results of amoxicillin or ampicillin alone versus amoxicillin or

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ampicillin plus gentamicin, although retrospective

Recommended therapy Alternative therapies
clinical data suggest that the addition of gentamicin can
reduce mortality.31 By contrast, in a cohort of 118 patients Streptococcus pneumoniae

with listeriosis, the aminoglycoside-treated group Penicillin MIC 006 g/mL Penicillin G or amoxicillin/ Cefotaxime, ceftriaxone, chloramphenicol
ampicillin
had increased rates of kidney injury and mortality.32
Penicillin MIC 012 g/mL
Trimethoprim-sulfamethoxazole is an alternative treat-
Cefotaxime or ceftriaxone Cefotaxime or ceftriaxone Cefepime, meropenem
ment in patients who are allergic to or intolerant of MIC <10 g/mL
penicillin. In a retrospective study,33 treatment with Cefotaxime or ceftriaxone Vancomycin plus either Vancomycin plus moxioxacin
trimethoprim-sulfamethoxazole plus ampicillin was MIC 10 g/mL cefotaxime or ceftriaxone
associated with a lower antibiotic failure rate and fewer Neisseria meningitidis
neurological sequelae than was the combination of Penicillin MIC <01 g/mL Penicillin G or amoxicillin/ Cefotaxime, ceftriaxone, chloramphenicol
ampicillin plus an aminoglycoside. ampicillin
Penicillin MIC 01 g/mL Cefotaxime or ceftriaxone Cefepime, chloramphenicol,
Streptococcus agalactiae uoroquinolone, meropenem
The standard approach to the treatment of meningitis Listeria monocytogenes Amoxicillin/ampicillin or Trimethoprim-sulfamethoxazole
penicillin G
caused by group B streptococci is amoxicillin or ampicillin
Streptococcus agalactiae Amoxicillin/ampicillin or Cefotaxime, ceftriaxone, vancomycin
or penicillin G combined with an aminoglycoside.4 penicillin G
Vancomycin and third-generation cephalosporins are Haemophilus inuenzae
alternatives. Some group B streptococci are less sensitive
-lactamase negative Amoxicillin/ampicillin Cefotaxime, ceftriaxone, cefepime,
to penicillin (MIC 01210 g/mL) than others; the chloramphenicol, aztreonam, uoroquinolone
optimum regimen for these isolates is not clear and the -lactamase positive Cefotaxime or ceftriaxone Cefepime, chloramphenicol, aztreonam,
ecacy of the third-generation cephalosporins in this uoroquinolone
setting has not been established.34 -lactamase negative, Meropenem Fluoroquinolone
ampicillin resistant
Haemophilus inuenzae Staphylococcus aureus
Since the emergence of -lactamase-producing and Meticillin sensitive Nafcillin or oxacillin Vancomycin, linezolid, daptomycin
chloramphenicol-resistant strains of H inuenzae, third- Meticillin resistant|| Vancomycin Trimethoprim-sulfamethoxazole, linezolid,
daptomycin
generation cephalosporins have become standard treat-
Staphylococcus epidermidis|| Vancomycin Linezolid
ment. Third-generation cephalosporins are more eective
than second-generation cephalosporins (eg, cefuroxime)35 Enterobacteriaceae** Cefotaxime or ceftriaxone Aztreonam, uoroquinolone,
trimethoprim-sulfamethoxazole,
and chloramphenicol, even in patients with H inuenzae meropenem, ampicillin
type b meningitis caused by chloramphenicol-sensitive Pseudomonas aeruginosa Ceftazidime or cefepime Aztreonam, meropenem, ciprooxacin
strains.36 The rates of isolation of -lactamase-producing Acinetobacter baumannii** Meropenem Colistin (usually formulated as
strains vary worldwide (15% in the UK, 26% in the USA, colistimethate sodium), polymyxin B
31% in France, and 42% in Spain), with high rates (42%)
MIC=minimum inhibitory concentration. *In the absence of clinical data, recommendations for use of some agents are
for non-typeable strains in the USA.4 Chloramphenicol based on cerebrospinal uid penetration and ecacy in experimental animal models of bacterial meningitis. In-vitro
resistance is also a concern in resource-poor settings, activities of -lactam antibiotic agents against S pneumoniae are predictable within drug classes, but the relation
where the drug is often used as rst-line therapy for between penicillin and cefotaxime-ceftriaxone MICs is not linear. Addition of rifampicin can be considered if the
organism is susceptible, the expected clinical or bacteriological response is delayed, or the cefotaxime/ceftriaxone MIC
patients with bacterial meningitis. In Japan, the
of the pneumococcal isolate is >40 g/mL. No clinical data exist for use of this agent in patients with pneumococcal
prevalence of -lactamase-negative ampicillin-resistant meningitis; recommendation is based on cerebrospinal uid penetration and in-vitro activity against S pneumoniae.
H inuenzae meningitis has increased rapidly from 6% in Addition of an aminoglycoside should be considered; might need intraventricular or intrathecal administration in
2000 to 35% in 2004; many of these strains are also Gram-negative meningitis. ||Addition of rifampicin should be considered. **Choice of a specic agent should be based
on in-vitro susceptibility testing. Might also need to be administered by the intraventricular or intrathecal routes.
resistant to ceftriaxone.37
Table 4: Antibiotics for bacterial meningitis after microorganism identication and in-vitro
Aerobic Gram-negative bacilli susceptibility testing*
The emergence of multidrug-resistant Gram-negative
bacilli is worrying, especially in patients with health-care-
associated bacterial meningitis.9 Resistance to the third- colistin (usually formulated as colistimethate sodium) or
generation and fourth-generation cephalosporins, and polymyxin B should be given intravenously, and might be
carbapenems, has reduced the range of antibiotic options given by the intrathecal or intraventricular route. In one
available. Outbreaks of meningitis caused by Escherichia retrospective study of 51 patients with Acinetobacter
coli strains producing extended-spectrum -lactamases in meningitis,39 all eight patients given a combination of
neonatal wards can be dicult to control.38 In patients with intravenous and intrathecal colistin survived.
Acinetobacter baumannii meningitis, the most commonly
used empirical antibiotic is meropenem with or without Staphylococcus aureus
gentamicin or amikacin given either intraventricularly or S aureus meningitis occurs mainly after neurosurgical
intrathecally.9 If the organism is resistant to carbapenems, procedures or placement of CSF shunts.9 Treatment

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should depend on the local prevalence of meticillin-
resistant S aureus; antistaphylococcal penicillins are
more eective than is vancomycin for the treatment of
severe S aureus disease, but empirical vancomycin can be
used until susceptibility testing results are ready.40
Duration of antibiotic therapy
Antibiotics need enough time to kill all the bacteria and
prevent disease recurrence, but the timescale of this
process varies widely and depends on the causative
bacteria, disease severity, and antimicrobial agent used.
Uncomplicated meningococcal disease can be treated
eectively with one intramuscular dose of ceftriaxone or
oily chloramphenicol, both of which are recommended
by WHO in African meningococcal meningitis epi-
demics.29,41 WHO recommends at least 5 days of
treatment in non-epidemic situations, in patients
younger than 24 months, or if fever, coma, or convulsions
last for longer than 24 h.41 In a meta-analysis of ve
controlled trials investigating shorter (47 days) versus
longer (714 days) antibiotic treatments for bacterial
meningitis, investigators noted no dierence in
outcome.41,42 In a controlled trial in 1027 children with
bacterial meningitis caused by S pneumoniae,
H inuenzae, or N meningitidis in Bangladesh, Egypt,
Malawi, Pakistan, and Vietnam, the investigators
reported no dierences in treatment failure or relapse
between 5 days versus 10 days of ceftriaxone treatment.43
Nevertheless, many authorities in high-income countries
recommend at least 7 days of treatment for haemophilus
and meningococcal meningitis, and 1014 days of
treatment for pneumococcal meningitis.3,6
New antibiotics for meningitis
The increasing prevalence of meningitis caused by
resistant bacteria has led to the consideration of new
antimicrobial agents for therapy, although data describing
their role are generally limited to extrapolations from
experimental animal models and case reports. We will
limit our discussion to agents that have been assessed in
patients with bacterial meningitis.
Cefepime
The fourth-generation cephalosporin cefepime has
broad-range activity and greater stability against
-lactamases, including those often produced by
Pseudomonas aeruginosa, than have agents from the
preceding generation (eg, ceftriaxone and cefotaxime).
Findings from experimental meningitis models and
some human studies suggested that cefepime could have
better CSF activity than ceftriaxone, including against
penicillin-resistant S pneumoniae;44,45 however, in two
controlled trials of 345 children with bacterial meningitis,
the investigators reported that cefepime has similar
ecacy to cefotaxime and ceftriaxone.44,45 The Infectious
Diseases Society of America (IDSA) guidelines recom-
mend cefepime as a second-line agent in the treatment
1698
of H inuenzae meningitis, and either cefepime or
ceftazidime as empirical rst-line treatment in patients
with post-neurosurgical meningitis.6
Carbapenems
Of the -lactams, the carbapenems possess the broadest
range of in-vitro activity against Gram-positive and
Gram-negative bacteria. Results from studies in human
beings suggest that meropenem has better CSF pene-
tration than do imipenem and doripenem.8,46 In four
controlled trials of 448 children and 58 adults, mero-
penem had similar ecacy and safety to cefotaxime or
ceftriaxone, making meropenem the carbapenem of
choice in the treatment of bacterial meningitis.8
The emergence of novel -lactamases with direct
carbapenem-hydrolysing activity has contributed to an
increased prevalence of carbapenem-resistant Entero-
bacteriaceae.47
Fluoroquinolones
The uoroquinolones gatioxacin and moxioxacin
penetrate the CSF eectively and have greater in-vitro
activity against Gram-positive bacteria than do their
earlier counterparts (eg, ciprooxacin). Findings from
experimental meningitis models suggested their ecacy
in S pneumoniae meningitis, including that caused
by penicillin-resistant and cephalosporin-resistant
strains.48,49 Although one controlled trial suggested the
uoroquinolone trovaoxacin mesilate to be as eective
as ceftriaxone, with or without the addition of vanco-
mycin, for paediatric bacterial meningitis,50 no clinical
trials describe the use of gatioxacin or moxioxacin to
treat bacterial meningitis in human beings. Trovaoxacin
and gatioxacin have been associated with serious
hepatic toxicity and dysglycaemia, respectively, and were
withdrawn from many markets.51 The IDSA guidelines
recommend moxioxacin as an alternative to third-
generation cephalosporins plus vancomycin for menin-
gitis caused by S pneumoniae strains resistant to penicillin
and third-generation cephalosporins,6 although some
experts recommend that this agent should not be used
alone but rather should be combined with another drug
(either vancomycin or a third-generation cephalosporin),
because of the absence of clinical data supporting its use.
Daptomycin
Daptomycin is a cyclic lipopeptide with solely Gram-
positive activity. Although it penetrates the CSF poorly,
experimental models indicate that CSF bactericidal
concentrations are achieved against most susceptible
organisms, and daptomycin could have greater bac-
tericidal activity than vancomycin against -lactam-
resistant bacteria.52 Human data are limited to case
reports that describe the successful use of daptomycin
(612 mg/kg once daily), usually combined with rifam-
picin, for meningitis caused by meticillin-resistant
S aureus and vancomycin-resistant Enterococcus spp.53,54
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Linezolid
Linezolid is an oxazolidinone that acts only on Gram-
positive bacteria. It has never been assessed in a
controlled trial in patients with bacterial meningitis,
although some case reports have been published;55
linezolid penetrates the CSF well and is associated with
cure rates of about 90%. Clinical studies have reported
variable CSF penetration; about 50% of patients given
standard doses (600 mg every 12 h) might not achieve
therapeutic CSF concentrations.56 Higher doses and CSF
concentration measurements might be needed to
optimise linezolid therapy for bacterial meningitis.
Tigecycline
Tigecycline is a glycycline antibiotic that is active against
many Gram-positive and Gram-negative bacteria. Data
about its use in bacterial meningitis are limited mainly
to case reports describing tigecycline treatment for
multidrug-resistant Acinetobacter meningitis,57 some of
which show that standard intravenous tigecycline doses
produce subtherapeutic CSF concentrations.57,58
Adjunctive dexamethasone therapy
Experimental animal models have shown that outcome
from bacterial meningitis is related to the severity of
inammation in the subarachnoid space and could
potentially be improved by modulation of the inam-
matory responseeg, with dexamethasone.59 Initial
trials suggested that dexamethasone reduced the risk of
hearing loss in children with H inuenzae type b
meningitis.60 Additional data extended the likely benet
to children with S pneumoniae meningitis if dexa-
methasone was given with or before the rst dose of an
antibiotic agent.60 However, subsequent randomised
controlled trials in Malawian and South American
children did not show a benet of dexamethasone.61,62 A
Cochrane meta-analysis published in 201060 showed that
adjunctive dexamethasone treatment did not reduce
mortality in children with bacterial meningitis, but did
decrease hearing loss from 20% in the control group to
15% in corticosteroid-treated children (risk ratio [RR]
074, 95% CI 062089). None of the included studies
investigated children younger than 1 month (neonatal
meningitis), and one randomised, but not placebo-
controlled, trial did not show a benet of dexamethasone
in neonates.63
For adults with community-acquired bacterial menin-
gitis, the results of a European controlled trial showed that
adjunctive dexamethasone, given before or with the rst
dose of antibiotic therapy, was associated with a reduced
risk of unfavourable outcome (15% vs 25%; RR 059, 95%
CI 037094) and a reduction in mortality (7% vs 15%,
048, 024096).64 This benecial eect was most obvious
in adults with pneumococcal meningitis, in whom the
mortality rate decreased from 34% to 14%. However,
randomised controlled trials in Malawi and Vietnam did
not show that dexamethasone beneted adult patients,65,66
www.thelancet.com Vol 380 November 10, 2012
Series
although the Vietnam trial66 did show that dexamethasone
increased survival in patients with microbiologically
conrmed bacterial meningitis.
Investigators of an individual patient data meta-analysis
of trials published since 2000 attempted to explain the
dierences between individual trial results.67 In this
analysis of 2029 patients of all age groups from ve trials,
treatment with adjunctive dexamethasone did not
signicantly reduce mortality, neurological disability, or
severe hearing loss in patients with bacterial meningitis.
There were no signicant treatment eects in any of the
prespecied subgroups. A post-hoc analysis suggested that
adjunctive dexamethasone treatment reduced the rate of
hearing loss in survivors (odds ratio [OR] 077, 95% CI
060099; p=004). Adjunctive dexamethasone treatment
was not associated with an increased risk of adverse events.
Guidelines recommend the use of adjunctive
dexamethasone in patients with suspected or proven
community-acquired bacterial meningitis, but only in
high-income countries.6,68 Dexamethasone treatment
should be started with or before the rst dose of antibiotics.
It should be given for 4 days at a dose of 06 mg per kg of
bodyweight intravenously every day for children, and
10 mg given intravenously every 6 h for adults. A controlled
study of 118 children with bacterial meningitis showed
2-day and 4-day regimens of dexamethasone to be similarly
eective.69 However, this study was underpowered, with
neurological sequelae or hearing loss occurring in 18%
and 38% of patients in the 2-day and 4-day regimen
groups, respectively. Dexamethasone should be stopped if
the patient is discovered not to have bacterial meningitis
or if the bacterium causing the meningitis is a species
other than H inuenzae or S pneumoniae, although some
experts advise that adjunctive treatment should be
continued irrespective of the causative bacterium.3 A
recent study showed that adjunctive dexamethasone is
widely prescribed for Dutch patients with meningococcal
meningitis and is not associated with harm.70
Adjunctive dexamethasone therapy has been imple-
mented on a large scale for patients with pneumococcal
meningitis in some settings. In a nationwide obser-
vational cohort study in the Netherlands,71 the drug was
given in 92% of meningitis episodes during 200609.
This observational study reported a decrease in mortality
from 30% to 20% after the introduction of adjunctive
dexamethasone therapy (absolute risk dierence 10%,
95% CI 417; p=0001).
Cognitive decits occur often after bacterial meningitis,72
and studies in animals have suggested that corticosteroids
can aggravate learning deciencies.59 A follow-up of the
European study in adults did not show dierences in
cognitive outcome between patients who received dexa-
methasone and those who received placebo.73
A potential rare complication of dexamethasone therapy
in pneumococcal meningitis is delayed cerebral thrombosis,
although a causal relation between this complication and
dexamethasone is dicult to establish.74 Delayed cerebral
1699
 Series
thrombosis can occur 719 days after hospital admission in
patients with excellent initial recovery.74
Studies published so far do not address two important
questions: is dexamethasone eective after the rst
antibiotic dose; and is dexamethasone eective in
patients with septic shock? In experimental pneumo-
coccal meningitis, CSF bacterial concentrations at the
start of treatment seemed to be a more important factor
aecting the antimicrobial-induced inammatory
response than the time when dexamethasone therapy
was started.75 An individual patient data meta-analysis
showed that dexamethasone reduced hearing loss,
irrespective of whether the drug was given before or after
antibiotics.67 In patients with bacterial meningitis and
severe sepsis or septic shock, the survival benet in
patients with pneumococcal meningitis who were given
adjunctive dexamethasone outweighed the risks asso-
ciated with high-dose steroids.71,76
Other adjunctive therapies
Glycerol is a hyperosmolar agent that has been used to
decrease intracranial pressure. Although glycerol had no
benecial eect in experimental meningitis models,59 a
randomised clinical trial in Finland suggested that this
drug might protect against sequelae in children with
bacterial meningitis.77 A randomised controlled trial of
654 children with bacterial meningitis in several South
American countries showed a signicant decrease in
sequelae.62 However, a randomised controlled trial of
265 Malawian adults with bacterial meningitis showed
that adjuvant glycerol was harmful and increased
mortality.78 In children, the evidence is insucient to
justify routine glycerol treatment, but a randomised
controlled trial of this topic is ongoing in Malawi
(NCT00619203).
Despite some reported benecial eects of monitoring
and lowering of intracranial pressure in patients with
bacterial meningitis,79 when and how it should be
undertaken is unclear.80 Randomised studies of various
strategies to lower intracranial pressure have not been
done. Nevertheless, in patients with impending cerebral
herniation, monitoring of intracranial pressure and use
of osmotic diuretics to lower intracranial pressure could
be considered, but outcomes are generally poor in this
critically ill group of patients.80
Antipyretic treatments are often administered in
severely ill patients, but their eect on outcome is
uncertain. In a randomised controlled trial of 723 children
with bacterial meningitis in Luanda, Angola, treatment
with paracetamol for the rst 48 h did not increase
survival.16 Active cooling leading to hypothermia has
benecial eects in animals with pneumococcal menin-
gitis.59 The results of a randomised clinical trial of
moderate hypothermia in patients with severe bacterial
meningitis are eagerly awaited (NCT00774631).
Patients with bacterial meningitis should be moni-
tored carefully. Seizures occur frequently and the high
1700
associated mortality rate means that the threshold at
which anticonvulsant therapy is started should be low.81
Blood glucose concentrations need to be monitored and
normoglycaemia achieved.82 The goal of uid manage-
ment should be to maintain a normovolaemic state; even
in patients with severe hyponatraemia, uid maintenance
therapy should be used, rather than uid restriction.3
Monitoring of kidney function is also important,
especially in patients who develop septic shock and in
those with pre-existing kidney disease. Repeat CSF
analysis should only be done in patients whose condition
has not responded clinically after 48 h of appropriate
antimicrobial therapy.
Novel therapeutic approaches
Investigators have used experimental meningitis models
to study whether outcomes can be improved by modu-
lation of damage caused by reactive oxygen species, or by
inhibition of caspase or other mediators in the inam-
matory, coagulant, or complement cascades.59 Because
bacteriolytic antibiotic regimens temporarily increase the
release of bacterial components, investigators have used
animal studies to explore the role of non-bacteriolytic
antibiotics in the treatment of bacterial meningitis.59 In a
genetic association study in patients with bacterial
meningitis,83 investigators reported that a common non-
synonymous single nucleotide polymorphism in the gene
for complement component 5 (C5) was associated with
unfavourable clinical outcome. Consistent with these
human data, C5a receptor-decient mice with pneumo-
coccal meningitis had decreased brain damage, and
adjuvant treatment with C5-specic monoclonal anti-
bodies prevented death in all wild-type mice with
pneumococcal meningitis.83
Conclusions and future challenges
Two main therapeutic strategies exist to improve the
outcome of patients with bacterial meningitis: optimisation
of antimicrobial killing with antibiotics, and reduction of
the inammatory response in the subarachnoid space with
adjunctive agents such as dexamethasone. Optimisation of
the antibiotic eect depends on active antibiotic therapy
being started early in infection, usually before the causative
bacterium and its antibiotic susceptibility are known.
Determination of which antibiotic agent will be most
eective is becoming ever more dicult in the face of
increasingly drug-resistant bacteria. Clinical data for new
antibiotics for bacterial meningitis have not kept pace with
the rise of resistance, and controlled trials exploring the
role of these agents are urgently needed. Dexamethasone
is the only accepted adjunctive therapy for the treatment of
patients with bacterial meningitis, but it has shown
obvious ecacy only in high-income countries. A greater
understanding of disease pathogenesis and patho-
physiology could explain why dexamethasone treatment
benets some patients with bacterial meningitis, but
not others, and could help to identify new adjunctive
www.thelancet.com Vol 380 November 10, 2012

therapeutic strategies. In the near future, controlled trials
are needed to assess treatment modalities such as
induction of hypothermia, intracranial pressure manage-
ment, and specic monoclonal antibodies. However, the
greatest eect on the burden of illness due to bacterial
meningitis is likely to be achieved through widespread use
of vaccinations.
Contributors
All authors contributed to writing and editing of the review, and all
authors approved the nal version.
Conicts of interest
We declare that we have no conicts of interest.
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